Objectives: Prader-Willi syndrome ( PWS) is characterized by infantile hypotonia, childhood obesity, growth hormone deficiency, short stature, and hypogonadotropic hypogonadism. Delayed pubertal development is usually detected in PWS, whereas central precocious puberty (CPP) is very rare in PWS. This study aimed to investigate the clinical and biochemical follow-up of PWS patients with CPP. Methods: A total 70 PWS patients was diagnosed with PWS by molecular genetic testing and clinical manifestations. Among them, 33 PWS patients (20 boys, 13 girls) aged 5-12 years were enrolled in the present study. Two individuals were confirmed as having UPD and 31 individuals had a deletion. Thirty-three PWS individuals have been treated with growth hormone (GH) for more than four years. Results: Among 33 PWS patients, five (15.1%) patients (2 boys, 3 girls) were diagnosed with CPP in whom a deletion was observed. CPP patients showed normal height and weight range for age but the growth rate was accelerated (8.7±0.6 cm/year). Physical examination revealed a Tanner stage II for breast/testicular development and a Tanner stage I for pubic hair development. Body mass index at gonadotropin-releasing hormone analog (GnRHa) start was 20.6±2.0. Routine hematological and biochemical analyses were normal. Endocrine evaluation revealed a random luteinizing hormone level of 0.3±0.3 IU/L, a follicle-stimulating hormone level of 3.7±2.9 IU/mL, and elevated DHEA-S 146.5±51.8 ug/dL. GnRH stimulation test was consistent with the diagnosis of CPP (LH peak 11.8 ±8.0 IU/L). Skeletal maturation, evaluated by a left wrist X-ray, was advanced, relative to chronological age, by 2.6±0.5 years according to the Greulich and Pyle method. Pituitary MRI scan was normal. Combined therapy with GnRHa and GH was done, the treatment was beneficial in terms of halting the progress of pubertal development. Conclusions: CPP tends to be underdiagnosed in PWS individuals during GH treatment. Considering high CPP-diagnosis rate (15.1%) in this study, thorough recognition and monitoring of pubertal development in PWS may be an important for the early diagnosis and individualized treatment of CPP.